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Abstract

Objective

To investigate the clinical characteristics of cardiac cephalalgia and determine whether there is a more suitable alternative criterion.

Method

Patients with cardiac cephalalgia diagnosed and treated from May 2019 to April 2021 in the First Affiliated Hospital of Zhengzhou University (Zhengzhou, China) were prospectively and consecutively collected, their clinical manifestations were analyzed, and compared with the 2018 diagnostic criteria.

Results

A total of 30 patients were collected, including 16 males and 14 females. The onset age ranged from 31 to 84 years old, with a mean of 64.6 ± 11.9 years. Headache was more common in unilateral or bilateral frontotemporal, and the nature of pain includes pulsating, dull, stuffy pain, throbbing and so on. 80.0% were moderate to severe, 70% lasted less than half an hour, 76.6% had chest pain, 70% had chest tightness, 63.3% had sweating, and 36.6% had nausea. After treatment with drugs or coronary angiogenesis, except for one death, headache was fully or partially relieved in 29 patients.

Conclusion

Cardiac cephalalgia is generally located in frontotemporal region, of moderate or severe intensity, with a pulsating or throbbing sensation, abating within 30 minutes, and has a good prognosis. Accompanying chest pain, chest tightness, and sweating should be included in the diagnostic criteria.

Keywords

Cardiac cephalalgia acute myocardial ischemia angina headache

Introduction

Cardiac cephalalgia is a rare, secondary headache disorder. Cardiac cephalalgia is described in the third edition of the International Classification of Headache Disorders (ICHD-3) (1) as occurring during an episode of myocardial ischemia, often presented with moderate to severe headache accompanied by migraine-like symptoms such as nausea and vomiting, aggravated with or without exercise, which can be relieved by nitroglycerine. In 1997, Lipton et al. (2) reported two cases of patients with strenuous exercise-induced headache that was relieved after rest. Neurological functions and imaging studies were normal in both cases. During exercise stress testing, the patients’ episodes of headache were associated with electrocardiographic changes, suggesting myocardial ischaemia. Three-vessel disease was found in both patients with coronary angiography. After myocardial revascularization, the patients’ headaches were completely relieved, and the concept of “cardiac cephalalgia” was proposed for the first time. There is no clear epidemiological data on this concept. In a study of 150 outpatients with angina, 6% had symptoms of a headache (3). Despite its low morbidity, the mortality rate of patients with cardiac cephalalgia is 12.5% (4/32) (4), which is much higher than the mortality rate of patients with angina and coronary heart disease without headache (9.8% and 4.8%, respectively) (5). There are also case reports of headache as the only characteristic of angina pectoris (6 –8), which may be misdiagnosed as headaches caused by neurological diseases, leading to delayed diagnosis or even long-term misdiagnosis. Therefore, angina pectoris requires the attention of clinicians.

Culić et al. (9) reported the presence of headache, along with other symptoms, in 5.2% of patients with acute myocardial infarction. Moreover, in 3.4% of these patients, headache was the primary complaint. However, detailed features of headache were not mentioned. Although there have been related reports in the past of moderate to severe headaches in variable locations, more than half of the patients do not have chest pain (4,10), and more detailed features, such as duration and accompanying symptoms, are incomplete. In addition, some scholars evaluated the diagnostic criteria, suggesting that the existing criteria do not have a good compliance rate (11), but better alternative criteria have not been proposed. We aimed to investigate the clinical features, laboratory and imaging results, and outcomes in a large cohort of patients with cardiac cephalalgia and to compare these results with the 2018 diagnostic criteria to determine whether there is a more suitable alternative criterion.

Methods

Study design and patients

Data for this study were obtained from the First Affiliated Hospital of Zhengzhou University (Zhengzhou, China), which is a large comprehensive tertiary centre. The data were collected prospectively and consecutively validated by the clinical team (including neurologists and cardiologists).

The target trial was defined as the clinical characteristics of patients with cardiac cephalalgia, including age, sex, age of onset, cardiovascular risk factors, location, nature, degree, duration, accompanying symptoms, possible triggers and mitigating factors, treatment and response, and related test results. After admission, 2 ml of fasting cubital venous blood samples were drawn from all patients and placed in an anticoagulation test tube for myocardial enzyme spectroscopy. A Cobas 8000 automatic biochemical immunoassay analyser (Roche) was used to measure lactate dehydrogenase (LDH) and creatine kinase (CK), creatine kinase cardiac muscle isoenzyme (CK-MB) and serum glutamic oxaloacetic transaminase (SGOT) levels. The same testing method is applicable to myocardial injury markers, such as myoglobin, troponin I, CK-MB, B-type natriuretic peptide BNP, N-terminal pro BNP NT-proBNP. All patients underwent electrocardiogram and coronary imaging examinations, including coronary CTA and/or coronary angiography (CAG), partially complete Holter electrocardiogram, cardiac colour Doppler ultrasound, exercise stress test and cardiac MRI examination. We followed all included patients from the time of diagnosis until death or November 2021.

Eligible patients were hospitalized in the cardiology department of our hospital and diagnosed with cardiac cephalalgia between May 2019 and April 2021. Patients with cardiac cephalalgia were defined according to the 2018 criteria of ICHD-3 (Table 1) (1). At the same time, in patients who did not describe headache as a symptom and were diagnosed with no cardiac ischemia or initially diagnosed with headaches related to possible cerebral ischemia, hypertension, inflammation and infection, and patent foramen ovale, the application of nitroglycerin were excluded. Patients with confirmed myocardial ischemia, accompanied by headache symptoms, were excluded if there was no temporal relation to the onset and resolution between both. Patients who did not describe headache as a symptom were also excluded.

Headache severity score: 0–10 points are used for scoring method, 3 points or less is mild pain; 4–6 points is divided into moderate pain; 7–10 points is divided into severe pain. Coronary artery stenosis classification and scoring standard: a diameter stenosis rate of 100% indicates complete lumen occlusion, ≥75% indicates severe stenosis, between 50% and 74% indicates moderate stenosis, and <50% indicates mild stenosis. Cardiovascular risk factors included (12) age ≥45/55 years old (male/female), hypertension, diabetes, hyperlipidaemia, smoking, obesity or overweight.

The Ethics Committee of the First Affiliated Hospital of Zhengzhou University approved this study (Number: 2021- KY-0739-002). All patients gave written consent for study participation.

Statistical analysis

Data were tabulated and statistical analysis performed using Excel (Microsoft). Continuous variables are expressed as mean ± standard deviation (SD), and categorical variables in n (%).

Results

General information

In our study, 12 000 patients were hospitalized in the cardiology department of our hospital from May 2019 to April 2021. We identified 418 patients with headache. Patient disposition and reasons for exclusion are displayed in the flow chart (Supplemental Material page 1). The final analysis includes data from 30 patients, including 16 males and 14 females. The age of onset was 31–84 years old, with an average of 64.6 ± 11.9 years, of which 26 cases (86.7%) were over 50 years old. All 30 cases had at least one cardiovascular risk factor, 11 of them were ≥45/55 years old (male/female), 18 had hypertension, 10 had hyperlipidaemia, 8 had diabetes, 8 had smoking history, and 17 cases of obesity or overweight.

Headache features

In our cohort of headache patients, headache characteristics reported by patients were moderate (11/30) and severe pain (13/30), located in the frontal (7/30) and temporal (7/30) regions, unilateral or bilateral. The headache was mainly pulsating (10/30) dull (5/30) and stuffy pain (5/30), lasting less than half an hour (21/30), induced by exertion, emotion and activities (20/30), including walking for 10–20 minutes, brisk walking for 1–2 minutes after a meal or climbing three flights of stairs and moving heavy objects. Headache-associated symptoms were typical chest pain (23/30), chest tightness (21/30) and sweating (19/30). Specific headache features are reported in Figure 1. The comparison of the clinical features of 30 patients with cardiac headache in this study and the diagnostic criteria of ICHD-3 is shown in Table 1.

Figure 1

The characteristics of 30 cases of cardiac cephalalgia.

Table 1

Comparison of clinical characteristics of 30 patients with cardiac headache and the diagnostic criteria of ICHD-3.

Diagnostic criteria of ICHD-3	n	Coincidence rate (%)
A. Any headache fulfilling criterion C	30	100
B. Acute myocardial ischemia has been demonstrated	30	100
C. Evidence of causation demonstrated by at least two of the following:
1. headache has developed in temporal relation to the onset of acute myocardial ischaemia	30	100
2. either or both of the following:
a) headache has significantly worsened in parallel with worsening of the myocardial ischaemia	30	100
b) headache has significantly improved or resolved in parallel with improvement in or resolution of the myocardial ischaemia	30	100
3. headache has at least two of the following four characteristics:
a) moderate to severe intensity	24	80
b) accompanied by nausea	11	36.6
chest pain*	23	76.6
chest tightness*	21	70
sweating*	19	63.3
vomiting*	2	6.6
c) not accompanied by phototophia or phonophobia	24	80
d) aggravated by exertion	30	100
4. headache is relieved by nitroglycerine or derivatives of it	18	100ⁱ
D. Not better accounted for by another ICHD-3 diagnosis.	30	100

ICHD-3: The International Classification of Headache Disorders, 3rd edition; *The above characteristics are not included in ICHD-3 diagnostic criteria. ⁱ: 18 cases used nitrates, and all of them were relieved.

Heart condition

24 cases had elevated myocardial enzymes and/or markers of myocardial injury, and 6 cases had normal test results for both. ECG revealed acute myocardial ischemia or myocardial infarction in 9 cases, 9 cases showed T waves or ST-T changes, 7 cases showed approximately normal range ECG, ECG of 4 cases indicated left or right bundle branch block, and 1 case indicated old myocardial infarction. With regard to echocardiography, 8 cases showed typical ventricular wall motion incoordination, 27 cases showed decreased left ventricular diastolic function, and 1 case showed no abnormality. 1 patient had a headache attack during a Holter electrocardiogram, and the synchronized electrocardiogram indicated a rapid heart rate-dependent generalized myocardial ischemia. 29 cases underwent angiography including CAG or coronary CTA, and the results showed single-vessel disease in 5 patients, double-vessel disease in 6 patients, and three-vessel or multivessel disease in 18 patients. There were 3 cases of moderate coronary artery stenosis, 15 cases of severe stenosis, and 11 cases of luminal occlusion. 29 cases were diagnosed as coronary atherosclerotic heart disease and 1 case was diagnosed as hypertrophic cardiomyopathy. In 6 patients with mild headache, 3 cases were with coronary artery occlusion (Supplemental Material page 2).

Treatment and prognosis

All patients were given symptomatic treatment with anti-myocardial ischemia drugs. 23 cases underwent angioplasty treatment including drug balloon and/or stent implantation. Headache was improved in 22 cases and partially improved in 1 case. Among the other 7 patients treated with drugs only, 5 cases improved, 1 case partially improved, and 1 case died. The patient who died, was female, 71 years old. Coronary angiography showed occlusion of the right coronary artery and severe stenosis of the anterior descending artery and left circumflex artery. After admission to the hospital, she was treated with nitrates, lipid-lowering drugs, β receptor blockers, vasodilators and antiplatelet drugs, the family members refused to let her undergo surgery and were discharged on their own. The patient died of aggravated heart disease outside the hospital.

Discussion

Our study shows that cardiac cephalalgia is generally located in frontotemporal region, unilateral or bilateral, activity-evoked, of moderate or severe intensity, with a pulsating or throbbing sensation, lasting less than 30 minutes and has a good prognosis. It should be mentioned that over 70% of patients presented with typical symptoms of myocardial ischemia, including chest pain and chest tightness, and 63.3% of patients presented with sweating.

In the past, it was believed that there was no specific location of headache (4). In a study by Wang et al. (13), the majority of headaches were in the occipital region, and our study showed that headaches were in the frontotemporal region (46.6%). This study found that most patients had autonomic symptoms, where more than half of the patients experienced sweating and one patient experienced a runny nose, salivation, and defecation, which were not reported in previous cases. Headaches accompanied by autonomic symptoms are easily misdiagnosed as trigeminal autonomic headaches. The mechanism of cardiac cephalalgia accompanied by autonomic symptoms may be the same as that of cluster headache which is now thought to involve synchronized abnormal activity in the hypothalamus, the trigeminovascular system, and the autonomic nervous system (14). Stimulation of the trigeminal system triggers the parasympathetic dilator pathway (15), and then the portion running through the parasympathetic outflow traverses the sphenopalatine (pterygopalatine) ganglion to reach the peripheral structure, causing autonomic symptoms in the lacrimal gland and nasal mucosa (16,17). The occurrence of predominant sites and autonomic symptoms in cardiac cephalalgia further confirm the nerve convergence hypothesis, suggesting that the trigeminal nerve plays an important role in its pathophysiology.

In 2004, Chen et al. (11) reported one patient with cardiac cephalalgia, reviewed cases reported in the English-language literature and evaluated the new diagnostic criteria of ICHD-2 on the basis of these reported cases (n = 22). They found that the proposed headache features were generally not satisfactory; in particular, nausea was the least commonly fulfilled criterion.

The diagnostic criteria applied to our patients demonstrated that nausea had the lowest rate of symptom compliance with all diagnostic criteria (36.6%). Furthermore, we found that the proportions of chest pain, chest tightness and sweating outside the diagnostic criteria (76.6%, 70%, and 63.3%, respectively) were higher than those of nausea. Previously reported patients have more prominent headaches, and only 50% of patients have headaches accompanied by typical angina pectoris (10). In our study, in patients with confirmed or suspected myocardial ischemia, we found that most patients had typical angina symptoms. This shows that headache symptoms may be neglected in patients with angina pectoris, perhaps because the headache symptoms are relieved after treatment for myocardial ischemia, and the patients themselves have not paid attention to it. Herein, we recommend that accompanying chest pain, chest tightness, and sweating be included in the diagnostic criteria.

Clarifying the relationship between myocardial ischemia and the appearance and resolution of headache is the key to diagnosis (Supplemental Material Table S1). Routine screening of myocardial enzymes, myocardial injury markers and ECG are also necessary. Although not all tests are positive (18), multiple tests can increase the positivity rate, especially when headache occurs. Some scholars suggest that cardiac monitoring could be performed at the same time for critically ill patients (19). In 2019, MacIsaac et al. (20) reported a case of episodic headache with chest pain. The cardiac and neurological examinations were normal, and the exercise test confirmed the diagnosis, but they did not mention whether the patient had a headache during the test.

In our study, one patient developed severe chest tightness and chest pain during the exercise test, indicating myocardial ischemia, but no headache. This suggests that headache may be related to the degree of myocardial ischemia. This is also consistent with the hypothesis of the myocardial ischemia threshold effect proposed by Chen et al. (11). In another case, a headache attack was monitored during a Holter recording, and the synchronized Holter recordings indicated myocardial ischemia, thus identifying the temporal correlation between the two. This suggests that long-term, multiple tests could help improve the diagnosis rate.

The relationship between the triggers, relieving factors/interventions and headache can also further clarify the diagnosis. The initial cases were presented with headaches that began after high-oxygen-consumption activities such as exercise, which were described as an “exertional headache” (2). However, in 2002, Gutiérrez-Morlote and Pascual (21) reported the first patient who had a headache onset during rest and proposed that cardiac cephalgia should not be restricted within the frame of headaches that are triggered by exercise. Wang et al. (13) summarized 35 reported patients and found that headaches in 18/24 was induced by exercise, agitation and sexual activity, and the other 11 cases did not mention the triggers. Our study is consistent with their results. In our study, both the induction and remission times, which were within half an hour, are in line with the characteristics of angina pectoris and the onset time of nitroglycerin, which further supported the diagnosis. Cardiac cephalalgia treatment is the same as the treatment of anti-angina pectoris of coronary heart disease and responds well to nitrate esters.

We believe these findings have important implications for clinical diagnosis. The association between headache and myocardial ischemia should be considered for patients more than 50 years old with new-onset, moderate to severe headaches accompanied by cardiovascular risk factors.

This study has limitations, such as relatively little evidence in evaluating the association between headache and myocardial ischemia, requiring multiple examinations during headache attacks, including ECG, Holter or myocardial enzymes, myocardial damage markers, or long-term ECG monitoring such as 24-hour Holter or ECG monitoring. In this regard, under the premise of acute myocardial ischemia, we combined the close relationship on the appearance and resolution between headache symptoms and myocardial ischemia symptoms and the response to nitroglycerin for diagnosis, which was then repeated multiple times in the follow-up combined with the treatment response to verify findings. Nonetheless, we identified the clinical symptoms of cardiogenic headache, supporting the important role of the trigeminal nerve in cardiac cephalalgia. Regarding the diagnostic criteria, we found that chest tightness, chest pain, and sweating had a higher compliance rate than nausea, and we suggest that they should be included in the diagnostic criteria.

Conclusions

Our prospective findings in 30 patients with cardiac cephalalgia showed that in addition to the typical migraine-like headache symptoms, most patients also have typical angina-related symptoms. For patients with new-onset, short-lasting, moderate-to-severe headache accompanied by one or more cardiovascular risk factors, the possibility of cardiac cephalalgia should be highly suspected, and details such as chest pain, chest tightness, etc. should be inquired about.

Clinical Implications

Cardiac cephalalgia is generally located in frontotemporal region, of moderate or severe intensity, with a pulsating or throbbing sensation, abating within 30 minutes and has a good prognosis.

The pathophysiology of cardiac cephalalgia remains obscure, but our data suggest it is related to cardiac afferent-trigeminal convergence.

Accompanying chest pain, chest tightness, and sweating should be included in the diagnostic criteria.

Supplemental Material

sj-pdf-1-cep-10.1177_03331024221088993 - Supplemental material for Clinical analysis of 30 cases of cardiac cephalalgia

Supplemental material, sj-pdf-1-cep-10.1177_03331024221088993 for Clinical analysis of 30 cases of cardiac cephalalgia by Jia Xu, Ningning Mao, Chengze Wang, Jilun Feng and Yajun Lian in Cephalalgia

Footnotes

Author contribution statement

Literature review, patient collection, patient follow-up and paper writing: Jia Xu, Ningning Mao, Chengze Wang, Jilun Feng; research guidance and paper revision: Yajun Lian.

Acknowledgements

We would like to acknowledge the contribution of Dr Chuanjie Wu in advising on the manuscript revision.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Supplemental material

Supplemental material for this article is available online.

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